The long-term goal of this project is to further our understanding of the underlying mechanisms leading to memory loss in Alzheimer's disease (AD). In this study, we propose to investigate the composition and mechanisms of action of beta-amyloid (A) assemblies disrupting learning and memory in mice and humans. We have previously demonstrated strong associations between A*56, an endogenously formed 56-kDa A assembly, and memory dysfunction in the Tg2576 APP transgenic mouse line and shown that purified A*56 disrupts cognitive function when injected into the lateral ventricles of young, healthy rats. Unpublished data revealed that A*56 physically interacts with NMDA receptor (NMDAR) complexes and evokes Ca2+ transients in primary neuronal cultures. In addition, we have detected multiple A oligomers including A*56 in humans at stages preceding clinical AD (i.e. pathological aging and mild cognitive impairment, MCI). Together, these observations have led us to propose that Alzheimer's disease begins as a disorder of synaptic function, triggered when A*56 disrupts NMDAR-mediated synaptic physiology. In parallel other A oligomers (dimers, trimers and A-derived diffusible ligands, ADDLs) have displayed specific synaptotoxic and/or cytotoxic effects. Of recent focus, A dimers were found in close association with amyloid plaques and are among the leading culprits mediating the neurotoxicity observed within the microenvironment of deposited amyloid, which has been proposed to underlie some aspects of dementia in AD. The diversity of these A-induced effects suggests that multiple oligomeric A species trigger specific mechanisms at different stages of the disease. Efforts to clarify this complex situation may reconcile disputes and resolve confusion concerning the relevance and significance of low-n versus high-n oligomers. The goal of the proposed study is to better understand the roles of distinct A oligomers in the pathogenesis and progression of AD. To test this hypothesis, four aims are proposed: 1) determine whether specific A oligomers are correlated with clinical status or cognitive decline in humans; 2) identify molecular targets of specific A oligomers; 3) determine whether and how A oligomers modulate NMDARs function in vitro; 4) examine how A oligomers affect NMDAR-dependent LTP in vivo.